tbuckley/cabot-search huggingface dataset:
An assessment of the provider financial risk impacts of adoption of biosimilars in the Medicare Oncology Care Model.
Authors: Joshua A. Roth, Basit Iqbal Chaudhry, Andrew Yue, John M. Kelton, Ahmed Shelbaya, Lisa Tran, Meng Li, Jingyan Yang
Journal: Journal of Clinical Oncology (2023)

6613 Background: In 2016, Medicare launched the Oncology Care Model (OCM)—a Value-Based Payment (VBP) initiative providing per-beneficiary prospective payment to providers, and performance-based financial incentives/risks based on cost of care in 6-month ‘episodes’ vs. risk-adjusted benchmarks for cancer patients receiving chemotherapy. Oncology biosimilars may play an important role in managing financial risk in the OCM and other VBP models, but the real-world impact remains uncertain. The objective of this study was to quantify the impact of biosimilar adoption on oncology provider financial risk under the OCM using real-world data. Methods: We estimated the impact of biosimilar adoption on provider financial risk from 2019 to 2021 by modeling the methods (episode framing, pricing, &amp; risk adjustment) of the OCM. Cancer episodes were identified from the 5% Medicare Limited Data Set (LDS). The study sample consisted of cancer treatment episodes with use of any of the following agents or their biosimilars: bevacizumab, rituximab, trastuzumab, epoetin alfa, filgrastim, and pegfilgrastim. Financial risk was defined as the difference in observed total cost of care vs. OCM target episode cost. The primary outcome was the difference in financial risk (expressed in nominal $USD) under observed use of reference and/or biosimilars vs. hypothetical use of 100% reference agent. Results: The study sample included 8851 6-month episodes initiating between 1/2019 and 6/2021. Biosimilar adoption resulted in a mean cost reduction of $1,020 per episode vs. hypothetical 100% use of reference agents. Biosimilar use increased markedly over the study horizon--with 24% of episodes with a biosimilar in Half (H)1 2019, increasing to 65% by H1 2021, and driven by increased use of antineoplastic (1% to 36%) vs. supportive care biosimilar agents (23% to 34%). Mean financial risk reduction grew with the rapid adoption of biosimilars over this period. The average risk reduction in episodes initiating in H1 2021 was about 10 times larger than that seen in episodes initiating in the H1 2019 ($2060 vs $201, See Table). Observed mean cost was below the OCM target cost ($48808) in H1 2021 but exceeded the target cost in all other periods (range: +$1451 to +$4966). Conclusions: From 2019 to 2021, rapid adoption of biosimilars in Medicare fee-for-service beneficiaries included in the LDS led to substantial cost savings and reduction in risk for cancer episodes evaluated under the OCM methods. Broad adoption of biosimilars is a key strategy that providers in oncology VBP models will need to consider to manage financial risk. [Table: see text]
Tumour factors and the variation in non-muscle invasive bladder cancer recurrence after transurethral resection surgery between sites: Results from the RESECT study.
Authors: Fortis Gaba, Kevin M. Gallagher, Nikita R. Bhatt, Keiran D. Clement, Eleanor F. Zimmermann, Sinan Khadhouri, Meghana Kulkarni, Thines Anbarasan, Alexander Ng, Alexander Light, Aqua Asif, Vinson W. Chan, Arjun Nathan, Sabrina H. Ross, Tim O'Brien, Steve MacLennan, Matthew E. Nielsen, Paramananthan Mariappan, Veeru Kasivisvanathan
Journal: Journal of Clinical Oncology (2023)

4510 Background: To determine if there is significant variation in early recurrence after transurethral resection (TURBT) surgery between sites taking part in the RESECT study (NCT05154084) after accounting for tumour characteristics. Methods: An international, multi-centre, observational study. A mixed effects logistic regression model with tumour size, tumour number, tumour grade, tumour stage as fixed effects and site as a random effect was fitted. Cases with first, presumed non-muscle invasive bladder cancer (NMIBC) undergoing TURBT were included. Cases were excluded if first check follow up had not been completed. Sites were excluded if they did not have at least 10 cases with first check follow up. Local and/or national approvals or ethical exemptions were obtained prior to commencing the study at participating sites. Results: After exclusions, 186 sites (UK: 80; Europe: 59; North America: 18; Asia: 17; Africa 7; South America: 3; Oceania: 2), contributing a total 4597 cases (average 25 cases) were included. Median recurrence rate per site was 12% (IQR 0-22) for low grade tumours and 27% (IQR 13-42) for high grade tumours. After controlling for tumour size, number, stage and grade (all significantly and independently associated with early recurrence) there was significant residual variation attributable to site (p&lt;0.0001, intra-class correlation, 0.1). Adjustment for sites improved the regression model from an area under the receiver operating characteristic curve of 0.66 to 0.74. Initial analysis of surgical and peri-operative practice showed wide variation, mean 75% (IQR 66-92) cases per site had detrusor muscle resection and 42% (IQR 17-58) had use of single instillation of intravesical chemotherapy. Other differences in operative and perioperative practice were identified through surveys. Conclusions: There is significant variation in the early recurrence rate of NMIBC after TURBT surgery between sites that could not be explained by currently understood tumour features. We have identified differences in surgical technique and perioperative practice that may impact this and further investigation is warranted to understand how these factors impact recurrence rates. Clinical trial information: NCT05154084 . [Table: see text]
SAMHD1-induced endosomal FAK signaling promotes human renal clear cell carcinoma metastasis through activating Rac1-mediated lamellipodia protrusion.
Authors: Jin Young Kim, Sunho An, Seungmee Lee, Byung Hoon Kim, Sojin Shin, Misun Choe, Eunyoung Ha, Ji Hae Seo
Journal: Journal of Clinical Oncology (2023)

e16523 Background: Human sterile α motif and HD domain-containing protein 1 (SAMHD1) has deoxyribonucleoside triphosphohydrolase (dNTPase) activity that allows it to defend against human immunodeficiency virus type I (HIV-1) infections and regulate the cell cycle. Although SAMHD1 mutations have been identified in various cancer types, their role in cancer is unclear. Here, we aimed to investigate the oncogenic role of SAMHD1 in human clear cell renal cell carcinoma (ccRCC), particularly as a core molecule promoting cancer cell migration. Methods: HK-2 (#22190, a normal kidney cell line), Caki-1 (#30046), Caki-2 (#30047), SN12C (#80025), and ACHN (#21611) cells were obtained from the Korean Cell Line Bank (Seoul, Korea). SN12C and ACHN cells were transfected with siRNA targeting SAMHD1. From the Broad GDAC Firehose database ( https://gdac.broadinstitute.org/ ), we downloaded RNA-sequencing (RNA-seq) and clinical data from the pankidney cohort (KIPAN), clear cell renal cell carcinoma (KIRC, ccRCC in the present study), renal papillary cell carcinoma (KIRP, PRCC in the present study), and kidney chromophobe (KICH, chRCC in the present study) datasets. We analyzed 20 pairs of human tissues (tumor and normal specimens) from Dongsan Hospital. The results are expressed as the mean ± SD or SEM. We used a two-tailed Student’s t test for single comparisons or two-way ANOVA for multiple comparisons. Results: We found that SAMHD1 participated in endocytosis and lamellipodia formation. Mechanistically, SAMHD1 contributed to the formation of the endosomal complex by binding to cortactin. Thereafter, SAMHD1-stimulated endosomal focal adhesion kinase (FAK) signaling activated Rac1, which promoted lamellipodia formation on the plasma membrane and enhanced the motility of ccRCC cells. Finally, we observed a strong correlation between SAMHD1 expression and the activation of FAK and cortactin in tumor tissues obtained from patients with ccRCC. Conclusions: In brief, these findings reveal that SAMHD1 is an oncogene that plays a pivotal role in ccRCC cell migration through the endosomal FAK-Rac1 signaling pathway.
Final results from SAUL, a single-arm international real-world study of atezolizumab (atezo) in 1004 patients (pts) with pretreated locally advanced/metastatic urinary tract carcinoma (UTC).
Authors: Cora N. Sternberg, Yohann Loriot, Ernest Choy, Daniel Castellano, Fernando Lopez-Rios Moreno, Giuseppe Luigi Banna, Ugo De Giorgi, Cristina Masini, Aristotelis Bamias, Xavier Garcia del Muro, Ignacio Duran, Thomas Powles, Marija Gamulin, Friedemann Zengerling, Lajos Geczi, Craig Gedye, Robert A Huddart, Geetha Kandula, Pari Skamnioti, Axel S. Merseburger
Journal: Journal of Clinical Oncology (2023)

4569 Background: In the SAUL study (NCT02928406), clinical outcomes in a broad population were similar to findings from phase 3 trials of anti-PD-(L)1 in highly selected pts. We report the final analysis 4 y after enrolling the last pt. Methods: Eligible pts had locally advanced/metastatic urothelial or non-urothelial UTC that had progressed during or after 1–3 prior lines of therapy for advanced UTC (or within 12 months of [neo]adjuvant therapy). Unlike most phase 3 immunotherapy trials, pts with autoimmune disease (AID), ECOG PS 2, creatinine clearance (CrCl) ≥15–30 mL/min, and/or stable CNS metastases were eligible. Pts took atezo 1200 mg q3w until disease progression or unacceptable toxicity. The primary endpoint was safety. Secondary endpoints included overall survival (OS) and duration of response (DoR). Results: Among 997 treated pts, 10% had ECOG PS 2, 5% had CrCl &lt;30 mL/min, 4% had a history of AID, and 7% had 2–3 prior lines of therapy. At data cutoff (Dec 20, 2022; median follow-up 55 mo), 78% of pts had died. Median treatment duration was 2.8 mo (range 0–62 mo; mean 9.5 mo), 96 pts (10%) took atezo for &gt;3 y, and 68 (7%) for &gt;4 y. Grade ≥3 adverse events (AEs) occurred in 51%; AEs led to atezo discontinuation in 8%. We show outcomes overall and in key subgroups. OS was &gt;4 y in 136 pts (14%); 132 responders had OS &gt;2 y. Conclusions: After 55 mo median follow-up, median OS was 8.6 mo and 3-y OS was 21% in a real-world population including important understudied subgroups. Long-term safety data continue to support the tolerability of atezo in pts with complex comorbidities. AESIs were not increased in pts typically considered to be at increased risk of immune-related AEs. OS was similar to trials in highly selected pts. Ongoing analyses are characterizing pts with exceptional long-term outcomes. Clinical trial information: NCT02928406 . [Table: see text]
Plasma KIM-1 for preoperative prediction of renal cell carcinoma versus benign renal masses, and association with clinical outcomes.
Authors: Wenxin Xu, Anush Mukeria, Valerie Gaborieau, Samuel M. Niman, Xiaowen Liu, Ayumi Takakura, David Zaridze, Matthew L. Freedman, David F. McDermott, Toni K. Choueiri, Paul J. Catalano, Venkata Sabbisetti, Krishna Maremanda, Joseph Bonventre, Phillip Pierorazio, Nirmish Singla, Paul Brennan, Rupal Satish Bhatt
Journal: Journal of Clinical Oncology (2023)

e16518 Background: For patients with suspicious renal masses, it is often unclear which should receive an intervention versus initial surveillance. Both clear cell and papillary renal cell carcinoma overexpress kidney injury molecule-1 (KIM-1) due to their proximal epithelial cell of origin. We investigated whether plasma KIM-1 improves risk stratification of patients with suspicious kidney masses. Methods: Pre-nephrectomy plasma KIM-1 was measured in two independent cohorts of patients with renal masses. Cohort 1, from the prospective K2 trial, included 162 patients found to have ccRCC (cases) and 162 patients with benign renal masses (controls). Cohort 2 included 247 patients with small (cT1a) renal masses from an academic biorepository. Multivariable models were used to assess the relationship between pre-nephrectomy plasma KIM-1, surgical pathology, and subsequent clinical outcomes. Results: In cohort 1, plasma KIM-1 distinguished RCC versus benign masses with AUC-ROC 0.81 (95% CI: 0.76-0.86). In cohort 2 (cT1a renal masses), plasma KIM-1 distinguished RCC versus benign masses with AUC-ROC 0.74 (95% CI: 0.67 to 0.80). Among patients in cohort 2, the prevalence of malignancy was 97% among patients with the highest quartile of KIM-1 compared to 55% among patients with the lowest quartile of KIM-1. Plasma KIM-1 was higher in clear cell RCC and papillary RCC compared to other histologies (p&lt;0.001 in each cohort). Cohort 1 patients had prospective long-term follow-up, and higher pre-nephrectomy KIM-1 was associated with worse metastasis free survival (multivariable MFS HR 1.29 per unit increase in log KIM-1, 95% CI 1.10-1.53) and worse overall survival (multivariable OS HR 1.31 per unit increase in log KIM-1, 95% CI 1.10-1.54). Conclusions: In two independent cohorts of patients with renal masses, elevated baseline plasma KIM-1 is associated with higher risk of malignant pathology, worse metastasis free survival, and higher risk of death. Plasma KIM-1 may be a useful risk stratification tool for patients with suspicious kidney masses.
Trastuzumab-induced cardiotoxicity in breast cancer patients: A meta-analysis and review of the literature (2012-2022).
Authors: Fnu Anamika, Akshit Chitkara, Komal Saharan, Tushar Choudhary, Ujjwal Soni, Gabriella Angelina Harmon, Anwaar Saeed
Journal: Journal of Clinical Oncology (2023)

e24101 Background: Breast cancer (BC) is the most common type of cancer diagnosed, and 10-15% of BC patients develop a HER2-positive disease with a poor prognosis. In a previous meta-analysis of NCCTG N9831 and NSABP B-31 trials, treatment of early-stage HER2-positive BC patients with Trastuzumab and chemotherapeutic drugs improved overall survival by 37%. Trastuzumab-induced cardiotoxicity (TIC) is characterized by cardiac dysfunction, including decreased left ventricular ejection fraction (LVEF) and heart failure. Per package inserts, the incidence of TIC is 4-6 times higher than the control. An important risk factor for TIC is the administration of concomitant anthracycline chemotherapy. Several studies have reported that this treatment combination can significantly reduce LVEF compared to Trastuzumab alone. In this study, we compiled recent randomized controlled trials (RCTs) and clinical trial data to evaluate the incidence of cardiotoxicity in Trastuzumab-treated BC and study management guidelines specifically directed for TIC. This will help reduce the morbidity and mortality in these patients. Methods: Our search included PubMed, EMBASE, Web of Science, and Cochrane Library articles from July 2012 through July 2022. RCTs and clinical trials that used Trastuzumab as a therapy and reported its cardiotoxic effects were included. A random-effects model was utilized with Review Manager, and a P value &lt; 0.05 was considered significant. The entire analysis of treatment and control groups had various guideline-directed chemotherapies, including anthracycline-based regimens. Results: Our initial search yielded 26 results. After a full literature review by two independent reviewers, we selected four studies that included 1481 patients with cardiotoxicity data in the treatment and control groups. The analysis pooled from clinical trials showed that the odds of cardiotoxicity (specifically LVEF reduction) in patients treated with Trastuzumab were about seven times higher than the control group (OR 6.78, 95% CI 2.85-16.09, p-value &lt; 0.0001). The guidelines recommend withholding Trastuzumab for ≥ 16% absolute decrease in LVEF from pre-treatment values or an LVEF value below normal institutional limits and ≥ 10% absolute decrease in LVEF from pretreatment values. The safety of continuation or resumption of Trastuzumab in patients with TIC has not been studied, and there are no standardized management guidelines. Conclusions: We conclude in our study that the odds of TIC are increased by almost seven times compared to chemotherapy alone. In addition to just regular monitoring of these patients with history, physical examination, and determination of LVEF by echocardiogram or MUGA scan per protocol, there is a need to formulate guidelines for continuation or resumption of Trastuzumab in patients with TIC.
Prevalence of delta-like ligand 3 expression in small cell lung cancer.
Authors: Xerxes Pundole, Chia-Hsin Ju, Lauren C. Bylsma, Naushin Hooda, Naimisha Movva, Ehab Elkhouly, D. Gwyn Bebb, Jon Fryzek, Akhila Balasubramanian, Danielle Jandial, Anne-Marie C. Dingemans
Journal: Journal of Clinical Oncology (2023)

e20618 Background: Delta-like ligand 3 (DLL3), a ligand of the Notch-family, is a potential therapeutic target in small cell lung cancer (SCLC). High expression levels of DLL3 are observed in SCLC, however different methods and thresholds are used. A systematic literature review (SLR) was conducted to estimate the prevalence of DLL3 expression in SCLC. Methods: A comprehensive literature search was conducted in the PubMed, EMBASE, Web of Science, and Cochrane Library databases, as well as on clinicaltrials.gov, using a pre-specified search strategy. This SLR was conducted and reported following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. The protocol was registered in the International Prospective Register of Systematic Reviews (CRD42022351119). Prevalence of DLL3 expression was evaluated overall and by method of DLL3 assessment and positivity threshold. Results: Of the 30 studies that met our study inclusion criteria, 22 (73.3%) were observational and 8 (26.7%) were clinical trials. Most studies (N = 21, 70%) evaluated less than 100 patient specimens (range: 20 to 1,362 patient specimens). Twelve studies (40%) were conducted in Asia, six (20%) in Europe, five (17%) in North America, five (17%) were multi-country, one in Brazil, and geographical location was not reported in one study. DLL3 testing methods varied across studies, with immunohistochemistry (IHC) being used in 26 (86.7%) studies. Two studies used real-time polymerase chain reaction, one used quantitative mass spectrometry, and one study did not report the testing method. Thirteen of the studies (13/26, 50%) that evaluated DLL3 expression by IHC used the Ventana SP347 assay. DLL3 expression was evaluated at various thresholds of tumor cell staining and showed a wide range of expression, across studies (Table). Conclusions: The SLR findings indicate that most studies assessing DLL3 in SCLC have relied on IHC methodology. Despite the range of thresholds used for evaluating positivity, DLL3 is notably expressed in SCLC. The frequency and impact of aberrant DLL3 localization was not addressed in these studies and minimal data on comparison of IHC with other methodologies exists. Results of this SLR also highlight the need to define a standardized method and threshold of evaluating DLL3 expression. [Table: see text]
Is access to adjuvant treatments prioritized over therapies for metastatic cancer? The Israeli experience.
Authors: Nava Siegelmann-Danieli, Carmil Azran, Yael Topol, Daniel Landsberger, Nicky Liebermann, Ariel Hammerman
Journal: Journal of Clinical Oncology (2023)

e18599 Background: The Israeli National Insurance Law determines a uniform benefits package ('the Health Basket') for all residents. A public committee advises each year on which new medications should be added to the Health Basket, subject to the fixed annum budget allocated by the government for this purpose. The clinical benefit of the proposed health technologies is the committee's prime consideration; however, the committee also considers the professional medical societies' prioritizations, the expected budget impact, and other social and ethical aspects. Towards the annual discussions for 2023, 63 new indications for 41 cancer drugs were proposed for the annual update. Of those, 8 were for novel neo-adjuvant/ adjuvant indications, all given high priority ranks by the Israeli Oncologists Society based on the significant disease-free survival (DFS) figures from the phase III clinical trials. Varying the adjuvant treatment practice patterns based solely on DFS figures without available overall survival (OS) data has been in much debate recently between global key opinion leaders. We, therefore, aimed to evaluate whether the Israeli decision-makers have de-facto accepted the attitude of prioritizing budgets for adjuvant/neo-adjuvant therapies as the Israeli Oncologists Society recommended. Methods: We collected data on all cancer therapies proposed for inclusion in the 2023 Health Basket update; drug name, indication, treatment setting (curative intent vs. metastatic disease therapy), ESMO-MCBS grade, and whether or not accepted for reimbursement. All data were extracted from the official Israeli Ministry of Health website publications and press releases. Results: 20% of the allocated budget for updating the National Health basket for 2023 was provided to treat solid tumor cancers. 7 out of the 8 candidate therapies in the neo-adjuvant/adjuvant settings received reimbursement approval (88%) vs. 11 out of 55 therapies for advanced/ metastatic stages of disease (20%). 13 of the 16 candidate metastatic disease therapies that had a high ESMO-MCBS score (4 or 5) were not approved for reimbursement in the 2023 annual committee discussions. Conclusions: Our retrospective evaluation of the Israeli reimbursement prioritization process reveals that decision-makers have accepted the approach of prioritizing potentially curative adjuvant therapies over treatments for patients with incurable cancer. In an era of prosperity of adjuvant therapies in a range of tumor types, concerns might arise regarding restrictions on access to novel therapies for metastatic cancer, even those with proven benefits of significantly improving patients' OS and quality of life. Future analysis should determine the impact of this trend adopted by decision-makers in Israel on disease progression and overall survival in the real-world setting.